6-acylamino-3-cyclohexyl[1, 3]-benzoxazines



United States Patent O 3,133,919 6-ACYLAMlNO-S-CYCLOHEXYLH,3]- BENZOXAZINES Martin Eric Kuehne, Summit, N.J., assignor to Cilia Corporation, a corporation of Delaware No Drawing. Filed Sept. 8, 1960, Ser. No. 54,599 11 Claims. (iCl. 260244) The acyl radical is primarily the radical of a lower alkane carboxylic acid represented, for example, by acetic, propionic, pivalic acid and the like. Other acyl groups are those of monocyclic carbocyclic aryl carboxylic acids, primarily benzoic acid, or benzoic acid substituted by lower alkyl, e.g. methyl, ethyl and the like, lower alkoxy, e.g. methoxy, ethoxy and the like, halogeno, e.g. fluoro, chloro, bromo and the like, halogeno-lower alkyl, e.g. trifluoromethyl, or by any other equivalent substituents; these substituents may be attached to any of the positions available for substitution, and one or more than one of the same or of different substituents may be present. Monocyclic carbocyclic aryl-lower alkane carboxylic acids may also furnish acyl radicals; such acids are, for example, phenyl-lower alkane carboxylic acids, e.g. phenylacetic, diphenylacetic, dihydrocinnamic acid and the like, in which the aromatic portion may also contain one or more than one of the previously mentioned substituents, which may be attached to any of the positions available for substitution.

In addition to the acyl portion, the amino group may carry an additional substituent, such as, for example, an aliphatic radical, such as lower alkyl, e.g. methyl, ethyl, n-propyl, isopropyl and the like, a carbocyclic aryl radical, such as monocyclic carbocyclic aryl, e.g. phenyl or substituted phenyl, such as lower alkyl-phenyl, in which lower alkyl may represent methyl, ethyl and the like, lower alkoxy-phenyl, lower alkoxy standing for methoxy, ethoxy and the like, halogeno-phenyl, in which halogeno may represent fluoro, chloro, bromo and the like, halogeno-lower alkyl-phenyl, halogeno-lower alkyl representing primarily trifiuoromethyl, or other substituted phenyl radicals, or a carbocyclic aryl-aliphatic radical, such as monocyclic carbocyclic aryl-lower alkyl, particularly phenyl-lower alkyl, e.g. benzyl, l-phenylethyl, 2-phenylethyl, diphenylmethyl and the like, and analogous radicals in which the aryl portion may be substituted as previously shown.

The group R attached to the 2-position of the 1,3- benzoxazine nucleus, may represent hydrogen. It may also stand for a carbocyclic aryl radical, particularly monocyclic carbocyclic aryl, e.g. phenyl or substituted phenyl, in which one or more than one of the same or of different substituents may be present. Substituted phenyl radicals are, for example, halogeno-phenyl, in which halogeno represents fluoro, chloro, bromo and the like, halogenolower alkyl-phenyl, in which halogeno-lower alkyl represents primarily trifiuoromethyl, nitro-phenyl, acylaminophenyl, such as lower alkanoylamino-phenyl, in which alkanoyl represents acetyl, propionyl and the like, carboxyphenyl, carbo-lower alkoxy-phenyl, in which carbo-lower alkoxy stands for carbomethoxy, carbethoxy and the like, carbamyl-phenyl, cyano-phenyl or any other suitable substituted phenyl radical. Other radicals representing R are heterocyclic aryl, particularly monocyclic heterocyclic aryl, radicals, such as pyridyl, e.g. 2-pyridyl, 3-pyridyl,

sulfonic, hydroxyethane sulfonic, p-toluene sulfonic acid and the like.

Quaternary ammonium derivatives of the compounds of this invention are primarily those with lower alkyl halides, e.g. methyl, ethyl, n-propyl or isopropyl chloride, bromide or iodide and the like, di-lower alkyl-sulfates, e.g. dimethyl sulfate, diethyl sulfate and the like, lower alkyl lower alkane sulfonates, e.g. methyl or ethyl methane or ethane sulfonate and the like, lower alkyl lower hydroxy-alkane sulfonates, e.g. methyl 2-hydroxy-ethane sulfonate and the like, lower alkyl monocyclic carbocyclic aryl sulfonates, e.g. methyl p-toluene sulfonate and the like. Also included as quaternary ammonium compounds are the quaternary ammonium hydroxides, and the salts obtained by reacting such quaternary ammonium hydroxides with inorganic or, particularly, with organic acids, such as with those described hereinbefore as being suitable for the preparation of acid addition salts. Mono-, dior poly-quaternary ammonium compounds may be formed depending on the number of quaternary ammonium derivative-forming tertiary nitrogen atoms; for example, the nitrogen atom of the oxazine nucleus, as well as the nitrogen atom of a possible pyridyl group may take part in the formation of quaternary ammonium compounds.

Compounds of the present invention show quieting effects in pharmacological tests and may, therefore, be used as tranquilizing and sedating agents to counteract hyperactivity, nervousness, tension and the like.

The compounds of the present invention also show a retarding eflfect on the growth of experimentally planted, fresh or aged adenocarcinoma E. O. 771. They may, therefore, be used to suppress the growth of tumors of mammary origins, and thus relieve the host organism from the secondary effects of tumor growth, such as pain and pressure on neighboring organs.

It has also been found, that the compounds of this invention are substantially free from toxic effects and unwarranted side reactions, and are therefore very suitable for long-lasting treatments.

Outstanding pharmacological effects are shown by the 6-N-lower alkanoylamino-3-cyclohexyl-2-R '-1,3-benzoxazines, in which R stands for hydrogen, halogeno-phenyl and nitro-phenyl, the therapeutically acceptable acid addition, particularly mineral acid addition, salts and lower alkyl quaternary ammonium halides, sulfates and sulfonates thereof. Members of this group are the compounds of the formulae:

WW l 3 g1; V

and

3 in which R represents phenyl, halogeno-phenyl, especial- 1y chlordphenyl, or nitro-phenyl, particularly the compound of the formula:

the therapeutically acceptable hydrohalic acid addition salts of such compounds, as well as the lower alkyl halides, particularly methohalides, thereof, which may be represented by the compound of the formula:

WW i N in which Hal represents halogen, e.g. chlorine, bormine, iodine and the like.

The new compounds of this invention may be used in the form of preparations, which contain the new benzoxazines, the salts or the quaternary ammonium compounds thereof in admixture with an organic or inorganic, solid or liquid carrier suitable for enteral, e.g. oral, or parenter al administration. For making up the preparations there can be employed substances which do not react with the new compounds, such as water, gelating, lactose, starches, stearic acid, magnesium stearate, stearyl alcohol, talc, vegetable oils, benzyl alcohols, gums, propyleneglycol, polyalkylene glycols or any other known carrier for medi caments. The preparations may be in the solid form, for example, as capsules, tablets, dragees and the like, or in liquid form, for example, as solutions, suspensions, emulsions and the like. If desired, they may contain auxiliary substances such as preserving agents, stabilizing agents, wetting or emulsifying agents, salts for varying the osmotic pressure, buffers and the like. They may also contain, in combination, other therapeutically useful substances.

The 6-acylamino-3-cyclohexyl-2-R -1,3-benzoxazines of this invention, in which R represents hydrogen, i.e. in which the 2-position is unsubstituted, salts or quaternary ammonium compounds thereof, may be prepared by reacting a phenol, which contains in the 4-position an acylamino group or a group capable of being converted into an acylamino group, with about one equivalent amount of hexylamine and with at least two equivalent amounts of formaldehyde or a reactive derivative thereof, and, if necessary, converting in a resulting 3-cyclohexyl-1,3-benzoxazine, which contains in the 6-position a group capable of being converted into an acylamino, such group into an acylamino group, and/or, if desired, converting a resulting salt into a free compound, and/or, if desired, converting a resulting compound into a salt or a quaternary ammonium compound thereof.

The reaction is preferably carried out in the presence of diluents, particularly of water-miscible, polar solvents, for example, alcohols, such as lower alkanols, e.g. methanol, ethanol, n-propanol, isopropanol and the like, ethers, e.g. tetrahydrofuran, p-dioxan, diethyleneglycol dimethylether and the like-ketones, e.g. acetone, ethyl methyl ketone and the like, carboxylic acid amides, e.g. formamide, N,N-dimethylformamide and the like, or water or mixtures of such solvents, as well as less polar solvents, such as aliphatic hydrocarbons, e.g. hexane and the like, carbocyclic aryl hydrocarbons, e.g. benzene, toluene and the like, or any other suitable solvents.

Normally, the amine and the phenol are given to the solution of the formaldehyde, which may be used as an aqueous solution thereof, or in the form of a polymer thereof, e.g. paraformaldehyde, trioxymethylene and the like, or of an acetal thereof with a lower alkanol, e.g. methanol, ethanol and the like, such as a di-lower alkoxymethane, e.g. dimethoxymethane, diethoxymethane and the like, or any other formaldehyde furnishing reagent.

If necessary, the reaction mixture is heated, for example, on the steam bath to about -90 for a short period, i.e. for from about five minutes to about one hour, if desired, in the atmosphere of an inert gas, e.g. nitrogen.

The resulting benzoxazine compound may be isolated according to known procedures. For example, the product may crystallize upon cooling, or upon diluting the reaction mixture with a solvent differing from the one used in the reaction; it may also be obtained by evaporating the solution and crystallizing the residue, or by extraction. The reaction product may be purified according to known methods, for example, by crystallization, recrystallization, adsorption, for example, on aluminum oxide, and elution, or any other suitable purification method.

The starting materials are known and are prepared according to known procedures. The starting material may contain a group capable of being converted into an acylamino group; such group is, for example, a nitro group or an unsubstituted amino group. In a resulting benzoxazine compound, such group may be converted into the desired acylamino group by reduction of a nitro group, for example, with hydrogen in the presence of a catalyst, e.g. Raney nickel and the like, or any other suitable reducing procedure, and/ or acylation of the amino group, for example, by treatment with a carboxylic acid halide, e.g. acetyl chloride and the like, a carboxylic acid anhydride, e.g. acetic acid anhydride and the like, a ketene, e.g. ketene and the like, or any other suitable acylating reagent.

The compounds of the present invention particularly those 6-acylamino-3-cyclohexyl-2-R -l,3-benzoxazines, in which R represents hydrogen, carbocyclic aryl or heterocyclic aryl, salts or quaternary ammonium compounds thereof, may also be prepared by reacting a 2-(cyclohexylaminomethyl)-phenol, which contains in the 4-position an acylamino group or a substituent capable of being converted into an acylamino group, or a salt thereof, with an aldehyde of the formula R CHO, in which R has the previously given meaning, or a reactive derivative thereof, and, if necessary, converting in a resulting 3- cyclohexyl-2-R -l,3-benzoxazine compound, which contains in the 6-position a group capable of being converted into an acylamino group, such group into an acylamino group, and, if desired, carrying out the optional steps.

The above reaction is carried out as previously shown; a dehydrating reagent, such as calcium sulfate, magnesium sulfate and the like, may be added to the reaction mixture. The aldehyde may also be used in the form of an acetal thereof, or, in the case of formaldehyde, in

the form of a polymer thereof.

The starting material used in the modified procedure may be prepared, for example, by treating a phenol, which contains in 4-position an acylamino group or a substitueht capable of being converted into an acylamino group, with at least one equivalent amount of cyclohexylamine and about one equivalent amount of formaldehyde or a derivative thereof. The reaction is preferably carried out in the presence of a solvent, such as one of those previously mentioned, and according to the above-mentioned conditions.

The starting material may also be prepared, for example, by treating a 6-acylamino-3-cyclohexyl-l,3-benzoxazine, particularly a 2-unsubstituted 6-acylamino-3 cyclohexyl-l,3-benzoxazine, with a strong acid, particularly a mineral acid, e.g. hydrochloric acid and the like, in the presence of water, a lower alkanol e.g. ethanol and the like, or any other suitable diluent; the desired 6-acylamino-2-(cyclohexylaminomethyl)-phenol may be isolated in the form of an acid addition salt thereof, which may be utilized directly in the above ring closure reaction. This latter procedure is particularly appropriate for the preparation of 1,3-benzoxazines, in which the 2-position is substituted by one of the previously mentioned radicals.

The compounds of this invention can be obtained in the form of the free bases or as the salts thereof. A salt may be converted into the free base, for example, by reaction with an alkaline reagent, such as an alkali metal hydroxide, e.g. lithium, sodium or potassium hydroxide, an alkali metal carbonate, e.g. sodium or potassium carbonate or hydrogen carbonate, ammonia, anion exchange resin and the like. A free base may be converted into its therapeutically useful acid addition salts by reaction with one of the inorganic or organic acids outlined hereinbefore; for example, a solution of the free base in a suitable solvent, such as a lower alkanol, e.g. methanol, ethanol, propanol, isopropanol and the like, a monocyclic carbocyclic aryl hydrocarbon, e.g. benzene, toluene and the like, an ether, e.g. diethylether and the like, a halogenated aliphatic hydrocarbon, e.g. methylene chloride and the like, or in a mixture of such solvents, may be reacted with the acid or a solution thereof and the desired salt may then be isolated.

Quaternary ammonium derivatives of the compounds of this invention may be obtained, for example, by reacting the tertiary base with an ester formed by a lower alkanol and a strong inorganic or organic acid. Such acids are more especially mineral acids, e.g. hydrochloric, hydrobromic, hydriodic, sulfuric acid and the like, or strong organic sulfonic acids, for example, lower alkane sulfonic acids, e.g. methane or ethane sulfonic acid and the like, or lower hydroxy-alkane sulfonic acids, e.g. 2-hydroxy-ethane sulfonic acid and the like. Useful reactive esters are, for example, lower alkyl halides, e.g. methyl, ethyl, n-propyl or isopropyl chloride, bromide or iodide and the like, di-lower alkyl sulfates, e.g. dimethyl sulfate, diethyl sulfate and the like, lower alkyl lower alkane sulfonates, e.g. methyl or ethyl methane or ethane sulfonate and the like, or lower alkyl lower hydroxy-alkane sul fonates, e.g. methyl 2-hydroxy-ethane sulfonate. The quaternizing reaction may be performed in the absence or in the presence of a solvent, under cooling, at room temperature or at an elevated temperature, at atmospheric pressure or in a closed vessel under pressure, and, if de sired, in the atmosphere of an inert gas, e.g. nitrogen. Suitable solvents are more especially lower alkanols, e.g. methanol, ethanol, propanol, isopropanol, butanol, pentanol and the like, lower alkanones, e.g. acetone, methyl ethyl ketone and the like, organic acid amides, e.g. formamide, dimethylformamide and the like, monocyclic carbocyclic aryl hydrocarbons, e.g. benzene and the like, halogenated hydrocarbons, e.g. methylene chloride and the like, ethers, e.g. diethyl ether and the like, or any other equivalent solvent.

Quaternary ammonium compounds obtained may be converted into the corresponding quaternary ammonium hydroxides, for example, by reacting a quaternary ammonium halide with silver oxide or a quaternary ammonium sulfate with barium hydroxide, by treating a quaternary ammonium salt with an anion exchanger, or by electrodialysis. From a resulting quaternary ammonium base there may be prepared therapeutically suitable quaternary ammonium salts by reaction with acids, for example, with those outlined hereinbefore for the preparation of the acid addition salts or with mono-lower alkyl sulfates, e.g. methyl sulfate, ethyl sulfate and the like. A quaternary ammonium compound may also be converted directly into another quaternary ammonium salt with the formation of the quaternary ammonium hydroxide; for example, a quaternary ammonium iodide may be converted into the corresponding chloride by treatment with hydrochloric acid in anhydrous methanol.

The invention also comprises any modification of the process wherein a compound obtainable as an intermediate at any stage of the process is used as starting material and the remaining step(s) of the process is(are) carried out, as well as any new intermediates.

In the process of this invention such starting materials are preferably used which lead to final products mentioned in the beginning as preferred embodiments of the invention.

This application is a continuation-in-part application of my application Serial No. 850,998, filed November 5, 1959, now abandoned.

The following examples are intended to illustrated the invention and are not to be construed as being limitations thereon. Temperatures are given in degrees centigrade.

Example 1 To a solution of 0.1 g. of potassium hydroxide in 10 ml. of methanol is added 6.0 g. of trioxymethylene; the resulting suspension is warmed, until a complete solution is obtained, and the solution is then cooled in ice. 9.9 g. of cyclohexamine is added while cooling, followed by 15.1 g. of 4-acetylamino-phenol. The mixture is heated at for fifteen minutes, then cooled and poured into 1000 ml. of water. The organic material is extracted with five portions of methylene chloride of ml. each and the organic layers are concentrated under reduced pressure to yield a crystalline residue. The pure 6-acetylamino-3-cyclohexyl-1,3-benzoxazine, M.P. 139, is obtained by recrystallization from ethyl acetate; yield: 25 percent.

By substituting in the above reaction 4-propionylaminophenol and 4-benzoylamino-phen-ol for the 4-acetylaminophenyl, the 3-cyclohexyl-6-pro-pionylamino-1,3-benzoxazine and 6-benzoylamino-3-cyclohexyl-1,3-benzoxazine, respectively, are obtained.

Example 2 A solution of 6.0 g. of 6-acetylamino-3-cyclohexyl-1,3- benzoxazine in 30 ml. of methylene chloride and 10 ml. of methyl iodide is kept at 25 for three days under an atmosphere of nitrogen. The resulting 6-acetylamino-3- cyclohexyl-l,3-benzoxazine methiodide is filtered oif and recrystallized from methanol, M.P. 233 yield: 100%.

The previously described 3-cyclohexyl-6-propionylamino-1,3-benzoxazine and 6-benzoylamino-3-cyclohexyl- 1,3-benzoxazine, when reacted with methyl iodide according to the above procedure, yield the desired 3-cyclohexyl- 6-propionylamino-l,S-benzoxazine methiodide and 6- benzoylamino-3-cyclohexyl-1,3 benzoxazine methiodide, respectively.

Example 3 5.0 g. of 6-acetyla mino-3-cyclohexyl-1,3-benzoxazine is dissolved in 50 ml. of methylene chloride and a stream of hydrogen chloride gas is passed through the solution until no further crystalline product is formed. The 6- acetylamino-3-cyclohexyl-1,S-benzoxazine hydrochloride is filtered off and washed three 20 ml. portions of methylene chloride, M.P. 180; yield: 100%.

Example 4 A mixture of 2.0 g. of 4-acetylamino-2-(cyclohexylaminomethyl)-phenol, 1.2 g. of 2-chloro-benzaldehyde and 2.0 g. of anhydrous calcium sulfate in 40 ml. of dry pdioxane is refluxed in an atmosphere of nitrogen for fifteen hours. The reaction mixture is filtered hot, concentrated to dryness, and the desired 6-acetylamino-2-(2-chlorophenyl)-3-cyclohexyl-1,3-benzoxazine is crystallized by adding benzene; yield: 1.1 g. It is purified by recrystallization from a mixture of methylene chloride and benzene, M.P. 183486.

By substituting in the above reaction 1.2 g. of 4-chlorobenzaldehyde for the 2-chloro-benzaldehyde, the 6-acetylamino-2-(4 chlorophenyl)-3-cyclohexyl-1,3-benzoxazine can be prepared, M.P. 161-162; yield: 1.6 g.

The starting material may be prepared as follows: 15 g. of 6-acetylamino-3-cyclohexyl-1,3-benzoxazine hydrochloride is dissolved in 250 ml. of water and allowed to stand at room temperature for four days. The crystalline 4-acetylamin0-2-(cyclohexylaminomethyl)-phenol hydrochloride hydrate is filtered off, M.P. 156157; yield: 80%. The free base is liberated by stirring a mixture of 14.0 g. of the salt in 50 ml. of warm water containing 4.5 g. of sodium bicarbonate for three hours. The 4- acetylamino-2-(cyclohexylaminomethyl)-phenol is filtered off and recrystallized from methanol, M.P. 163-164; yield 90%.

Example A solution of 1.2 g. of 4-acctylamino-2-(cyclohexylaminomethyD-phenol and 1.0 g. of benzaldehyde in 25 ml. of methanol is refluxed under an atmosphere of nitrogen for six hours. On concentration 1.3 g. of a crude product crystallizes, which is recrystallized from a mixture of methylene chloride and methanol to yield 6-acetylamino-3-cyclohexyl-2-phenyl-1,3-benzoxazine, M.P. 18- 184.

The benzaldehyde may be replaced in the above reaction by 4-nitrobenzaldehyde, 2-pyridine carboxaldehyde, 3- pyridine carboxaldehyde and 4-pyridine carboxaldehyde; the reaction of these aldehydes with 4-acetylamino-2-(cyclohexylaminomethyl)-phenol yields the 6-acetylamino-3- cyclohexyl-Z-(4-nitrophenyl)1,3-benzoxazine (M.P. 104 107, after recrystallization from benzene), 6-acetylamino- 3-cyclohexyl-2-(2-pyridyl)-1,3-benzoxazine (M.P. 197- 198, after recrystallization from methanol), 6-acetylamino-3-cycloheXyl-2-(3 pyridyl)-1,3-benzoxazine (M.P. 208-210", after recrystallization from methanol) and 6- acetylamino-3-cyclohexyl-2-(4 pyridyl)-1,3-benzoxazine (M.P. 162163, after recrystallization from methanol, with retention of methanol), respectively.

What is claimed is:

'1. A member selected from the group consisting of 6- acylarnino-3-cycl0hexyl-2-R -l,3-benzoxazine, in which acyl stands for the acyl radical of an acid selected from the group consisting of lower alkanoic acid and benzoic acid, and R is a member selected from the group consisting of hydrogen, phenyl, halogeno-phenyl, nitro-phenyl and pyridyl, a pharmaceutically acceptable acid addition salt and a lower alkyl quaternary ammonium salt thereof.

2. 6-N-lower alkanoyl-amino-3-cyclohexyl-2-R -1,3- benzoxazine, in which R stands for a member of the group consisting of hydrogen, halogeno-phenyl and nitrophenyl.

3. A pharmaceutically acceptable acid addition salt of 6-N-lower alkanoyl-amino-3-cycl0heXyl-2-R -1,3-benzoxazine, in which R stands for a member of the group consisting of hydrogen, halogeno-phenyl and nitro-plienyl.

4. A lower alkyl quaternary ammonium halide of 6- N-lower alkanoyl-amino-3-cycloheXyl-2-R '-1,3-benzoxazine, in which R stands for a member of the group consisting of hydrogen, halogeno-phenyl and nitro-phenyl.

5. 6-acetylarnino-3-cyclohexyl-1,3-benzoxazine.

6. 6-acetylamino-3-cyclohexyl-1,3-benzoxazine methohalide.

7. 6-acetylamino-3-cyclohexyl-1,3-benzoxazine methiodide.

8. 6 acetylarnino-3-cyclohexyl-1,3-benzoxazine hydrochloride.

9. 6 acetylamino-2-(2-chlor0phenyl)-3-cyclohexyl-1,3- benzoxazine.

10. 6-acetylamino-2-(4-chlorophenyl)-3-cyclohexy1-1,3- benzoxazine.

11. 6 acetylamino-3-cyclohexyl-2-(4-nitrophenyl)-1,3- benzoxazine.

References Cited in the file of this patent Burke: J.A.C.S., volume 71, pages 609-12 (1949). 

1. A MEMBER SELECTED FROM THE GROUP CONSISTING OF 6ACYLAMINO-3-CYCLOHEXYL-2-R1-1,3-BENZOXAZINE, IN WHICH ACYL STANDS FOR THE ACYL RADICAL OF AN ACID SELECTED FROM THE GROUP CONSISTING OF LOWER ALKONOIC ACID AND BENZOIC ACID, AND R1 IS A MEMBER SELECTED FROM THE GROUP CONSISTING OF HYDROGEN, PHENYL, HALOGENO-PHENYL, NITRO-PHENYL AND PYRIDYL, A PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALT AND A LOWER ALKYL QUATERNARY AMMONIUM SALT THEREOF. 